# NM_001039803.3(CDK20):c.843G>A (p.Lys281=)

https://sugi.bio/variant/cdk20-p-lys281

## Summary

**CDK20 p.Lys281= (c.843G>A)** is classified **Uncertain significance** in CDK20 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-29). Ultra-rare (popmax 0.0143%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0143%, sas)

## For patients & families {#patients}

This is a change in the CDK20 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDK20](https://sugi.bio/atlas/gene/CDK20/) |
| Protein change (HGVS p.) | p.Lys281= |
| Coding change (HGVS c.) | c.843G>A |
| MANE Select transcript | [NM_001039803](https://www.ncbi.nlm.nih.gov/nuccore/NM_001039803) |
| Variant type | single nucleotide variant |
| Location | chr9:87969194-87969194 (GRCh38) |
| ClinVar | [VCV4852897](https://www.ncbi.nlm.nih.gov/clinvar/variation/4852897/) |

**All HGVS expressions:** `NC_000009.11:g.90584109C>T`, `NC_000009.12:g.87969194C>T`, `NM_001039803.3:c.843G>A`, `NM_001170639.2:c.780G>A`, `NM_001170640.2:c.656G>A`, `NM_012119.5:c.780G>A`, `NM_178432.4:c.819G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.51) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.368, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 18.01**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.51**, acceptor gain **0.00**, donor gain **0.02**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.02**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.67** (loss), gain 0.07 / loss 0.67. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0143%** (sas) · FAF95 0.00844% · FAF99 0.00661% · 13/91,064 in the highest group · 14/1,613,670 alleles overall — ultra-rare (popmax 0.0143%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0143% | 7,005 |
| European (non-Finnish) | 8.48e-05% | 1,179,814 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CDK20** population constraint: LOEUF 1.342, pLI 1.4576e-14, missense-Z -1.0434. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **281** lies in the protein kinase domain; a UniProt-annotated variant site (in).

AlphaFold model confidence (whole protein): pLDDT 86.08, 64% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-05-29.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Care4Rare-SOLVE, CHEO | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-05-29 |

**Reported phenotype names (ClinVar):** See cases.

## Similar variants {#similar}

Related CDK20 variant pages (same residue, condition, or type): [CDK20 p.Lys281Glu](/variant/cdk20-p-lys281glu), [CDK20 p.Lys281Arg](/variant/cdk20-p-lys281arg), [CDK20 p.Phe204Leu](/variant/cdk20-p-phe204leu), [CDK20 c.189+23G>C](/variant/cdk20-c-189-plus-23g-c), [CDK20 c.378+19C>T](/variant/cdk20-c-378-plus-19c-t), [CDK20 c.564-44C>T](/variant/cdk20-c-564-minus-44c-t), [CDK20 c.688-214G>A](/variant/cdk20-c-688-minus-214g-a), [CDK20 c.76-20G>T](/variant/cdk20-c-76-minus-20g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4852897). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*